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New HCV Nucleotide PSI-7851
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from Pharmasset Sept 25 2009
PSI-7851 is a pro-drug of a nucleotide analog and is currently in development for the treatment of chronic HCV infection. PSI-7851 has demonstrated in vitro anti-HCV activity with EC50 values of approximately 90 +/- 60 nM, which is approximately 15- to 20- fold more potent than the active metabolite of our first generation nucleoside polymerase inhibitor, PSI-6130. The half-life of the triphosphate (the biologically active form of the molecule) in primary human hepatocytes is approximately 38 hours, which suggests the possibility for once-daily dosing. Like RG7128, PSI-7851 has demonstrated in vitro activity against HCV genotypes 1, 2, 3 and 4.
During March 2009, we initiated a Phase 1 study for PSI-7851. As part of the Phase 1 study, we completed a single ascending dose study that assessed the safety, tolerability and pharmacokinetics of PSI-7851 in healthy subjects at doses ranging from 25mg to 800mg. Preliminary results from this study indicated there were:
* No serious adverse events or discontinuations;
* No dose-related adverse events;
* No grade III/ IV lab abnormalities; and
* No clinically significant changes in vital signs or ECGs.
During June 2009, we initiated a Phase 1 multiple ascending dose study in HCV-infected patients. Subjects were enrolled at two U.S. centers and randomized to PSI-7851 (8 per cohort) or placebo (2 per cohort). The primary objective of this study was to assess the safety, tolerability, and pharmacokinetics of PSI-7851 after once-daily dosing for three days. The secondary objective of this study was to assess antiviral activity by measuring the change in HCV RNA. Three dose cohorts of PSI-7851 (50mg QD, 100mg QD, and 200mg QD) were evaluated. Preliminary results from this study indicated:
* PSI-7851 was generally safe and well tolerated across all cohorts with no discontinuations, no serious adverse events, and no dose-related trends in adverse events or laboratory abnormalities.
* PSI-7851 demonstrated potent antiviral activity with a mean HCV RNA decrease of -0.49 log IU/mL, -0.61 log IU/mL, and -1.01 log IU/mL in patients receiving 50mg QD, 100mg QD, and 200mg QD, respectively.
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